tbuckley/cabot-search huggingface dataset:
MEDB-38. Significance of CSF cytology and neurologic deterioration in relapsed medulloblastomas in the German HIT-REZ-97/-2005 Studies and the HIT-REZ-Register
Authors: Sebastian Tschirner, Jonas E Adolph, Christine Gaab, Stephan Tippelt, Ruth Mikasch, Martin Mynarek, Stefan Rutkowski, Thorsten Pietsch, Brigitte Bison, Monika Warmuth-Metz, Stefan M Pfister, Till Milde, Kristian W Pajtler, Olaf Witt, Michael Frühwald, Christof Kramm, Paul-Gerhardt Schlegel, Rolf-Dieter Kortmann, Stefan Dietzsch, Beate Timmermann, Gudrun Fleischhack
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Follow-up examinations are an essential part of the aftercare of patients with brain tumours. We investigated survival in relation to neurological impairment and positive CSF findings at first relapse/progression of medulloblastomas. METHODS: We collected data from patients with relapsed medulloblastoma from the German HIT-REZ studies (HIT-REZ-1997, HIT-REZ-2005, HIT-REZ-Register, n=342). Survival differences dependent on tumour cell-positive and -negative CSF cytology as well as on new onset or worsening of neurological impairment (i.e. headache, nausea/vomiting, ataxia, seizures and others) were analysed. RESULTS: 247 patients with a recurrent medulloblastoma were evaluable for CSF cytology at first relapse/progression (positive n=97, negative n=150). Patients with tumour cell-positive CSF results showed a significantly shorter median PFS and OS time compared to patients with negative CSF cytology [PFS: 9.1 (CI: 5.3-12.9) vs. 16.8 (CI: 13.8-19.8) months, plog rank test=0.001; OS: 14.4 (CI: 12.3-16.4) vs. 41.8 (CI: 33.3–50.4) months, plog rank test&amp;lt;0.001]. The shortest PFS and OS were observed in SHH-activated (n=18) and group 3 medulloblastomas (n=23) independently of CSF cytology result [median PFSSHH: 4.3 (CI:1.1-12.2), OSSHH: 6.3 (CI:1.1-18.7); PFSgroup3: 4.2 (CI:2.3-13.1), OSgroup3: 13.2 (CI:7.1-18.5) months]. For analysis of the impact of neurological deterioration on survival at first relapse, 249 Patients were evaluable. 105 patients with new or severely worsened neurological impairment at first relapse/progression displayed a significantly poorer PFS and OS time in comparison to 144 patients with unchanged or improved neurological symptoms [PFS: 8.2 (CI: 6.0-10.3) vs. 14.9 (CI: 12.0-17.9) months, plog rank test=0.001; OS: 15.1 (CI: 9.5-20.6) vs. 32.6 (CI: 26.2-38.4) months, plog rank test&amp;lt;0.001]. CONCLUSIONS: Patients with relapsed medulloblastoma show significantly worse survival (PFS and OS) in presence of positive CSF cytology or neurologic deterioration at relapse. These findings could be relevant for patient/parents counselling and treatment recommendations at relapse. Funded by the German Children Cancer Foundation
Three-Year Follow-Up of KTE-X19 in Patients With Relapsed/Refractory Mantle Cell Lymphoma, Including High-Risk Subgroups, in the ZUMA-2 Study
Authors: Michael Wang, Javier Munoz, Andre Goy, Frederick L. Locke, Caron A. Jacobson, Brian T. Hill, John M. Timmerman, Houston Holmes, Samantha Jaglowski, Ian W. Flinn, Peter A. McSweeney, David B. Miklos, John M. Pagel, Marie José Kersten, Krimo Bouabdallah, Rashmi Khanal, Max S. Topp, Roch Houot, Amer Beitinjaneh, Weimin Peng, Xiang Fang, Rhine R. Shen, Rubina Siddiqi, Ioana Kloos, Patrick M. Reagan
Journal: Journal of Clinical Oncology (2022)

Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). Outcomes after a 3-year follow-up in the pivotal ZUMA-2 study of KTE-X19 in relapsed/refractory MCL are reported, including for subgroups by prior therapy (bendamustine and type of Bruton tyrosine kinase inhibitor [BTKi]) or high-risk characteristics.Patients with relapsed/refractory MCL (one to five prior therapies, including prior BTKi exposure) received a single infusion of KTE-X19 (2 × 106 CAR T cells/kg).After a median follow-up of 35.6 months, the objective response rate among all 68 treated patients was 91% (95% CI, 81.8 to 96.7) with 68% complete responses (95% CI, 55.2 to 78.5); medians for duration of response, progression-free survival, and overall survival were 28.2 months (95% CI, 13.5 to 47.1), 25.8 months (95% CI, 9.6 to 47.6), and 46.6 months (95% CI, 24.9 to not estimable), respectively. Post hoc analyses showed that objective response rates and ongoing response rates were consistent among prespecified subgroups by prior BTKi exposure or high-risk characteristics. In an exploratory analysis, patients with prior bendamustine benefited from KTE-X19, but showed a trend toward attenuated T-cell functionality, with more impact of bendamustine given within 6 versus 12 months of leukapheresis. Late-onset toxicities were infrequent; only 3% of treatment-emergent adverse events of interest in ZUMA-2 occurred during this longer follow-up period. Translational assessments revealed associations with long-term benefits of KTE-X19 including high-peak CAR T-cell expansion in responders and the predictive value of minimal residual disease for relapse.These data, representing the longest follow-up of CAR T-cell therapy in patients with MCL to date, suggest that KTE-X19 induced durable long-term responses with manageable safety in patients with relapsed/refractory MCL and may also benefit those with high-risk characteristics.
An independent, root and branch review and reform of GMC processes is needed to ensure fairness in medical regulation
Authors: Chaand Nagpaul
Journal: BMJ (2022)

An independent, root and branch review and reform of GMC processes is needed to ensure fairness in medical regulation Chaand Nagpaul BMA council chairMany in the medical profession have rightly reacted with outrage at hearing that the Medical Practitioners Tribunal Service has suspended Manjula Arora, a GP in Manchester, relating to her request in December 2019 for a work laptop for the purpose of triaging patients. 1Astonishingly, Arora was suspended for "dishonesty" in using the single word "promised" in a phone call to her IT department, based on her understanding of an earlier email that a laptop would be provided when available.This was in spite of the fact that Arora had stated that the IT department should confirm her understanding of what she had been told.
Clinical and genomic characteristics of lung cancer concomitant chronic obstructive pulmonary disease (COPD).
Authors: Hongxia Ma, Qian Zhang, Qianqian Duan, Qin Zhang, Yuan Tan, Tingting Sun, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e15131 Background: Lung cancer and chronic obstructive pulmonary disease (COPD) often coexist. Lots of clinical and genomic descriptions related lung cancer have been investigated. However, the clinical and genomics characteristics of lung cancer coexisting COPD are still unclear. Herein, we explored the clinical characteristics and somatic mutational landscape of lung cancer coexisting COPD (COPD-LC) and compared with non-COPD Lung cancer (non-COPD-LC). Methods: We retrospectively collected total COPD-LC and non-COPD-LC patients who performed next generation sequencing (NGS) simultaneously from The Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University during December 2018 to August 2021. And collected COPD-LC data from TCGA to further analysis. COPD was defined as incompletely reversible airflow obstruction associated with post-bronchodilator forced expiratory volume in one second (FEV1) and its ratio to forced vital capacity (FEV1/FVC) &lt; 0.7. Results: Of the 139 patients enrolled in the study, 51 were categorized as COPD and 88 as non-COPD. In our clinical cohort, compared with non-COPD-LC, amount of male gender, older age and smoking patients were significantly higher than non-COPD in term of clinical data (all P &lt; 0.01). As for somatic mutation in our cohort, compared with non-COPD-LC, COPD-LC had higher mutation frequency of LRP1B (43% vs 9%, P = 0.001), EPHA5 (24% vs 1%, P = 0.002), PRKDC (14% vs 1%, P = 0.039) and PREX2 (14% vs 0%, P = 0.012), which had relationship with improved tumor immunity. Immunotherapy biomarker of PD-L1 positive expression (62.5% vs 52.0%, P = 0.397) and TMB (P = 0.004) also were higher in COPD group. Whereas, COPD-LC had lower frequency of EGFR (19% vs 50%, P = 0.013). And survival analysis showed in EGFR mutant patients with targeted therapy, COPD-LC had worse PFS than non-COPD-LC (HR = 3.52, 95%CI: 1.27-9.80, P = 0.01). TCGA cohort mutation data differed from the results of our cohort. In addition, RNA data from TCGA indicated COPD-LC increased tumor immunity. Conclusions: In our research, COPD-LC had unique clinical and molecular features. High PD-L1 expression and TMB indicated these patients may benefit from immunotherapy. Notably, mutation difference between Chinese and TCGA cohort and COPD-LC immunotherapy efficacy need prospective further study.
Who is shaping the future of urology? A descriptive analysis of current urology residency program directors
Authors: N. Corsi, S.E. Majdalany, I. Rakic, B. Friedman, M. Corsi, M. Butaney, T. Malchow, A.J. Piontkowski, K. Ginsburg, H. Atiemo, F. Abdollah
Journal: European Urology (2022)
Real-world clinical outcomes in patients receiving either ibrutinib or chemo-immunotherapy (CIT) as first-line (1L) treatment for chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL): A retrospective analysis.
Authors: Linda Wu, Tao Ran, Jinghua He, Sumeet Panjabi, Xiaoxiao Lu
Journal: Journal of Clinical Oncology (2022)

e19057 Background: Ibrutinib is an oral, once daily Bruton’s tyrosine kinase inhibitor and is the only targeted treatment that has demonstrated progression-free survival and overall survival in multiple phase 3 trials across age, fitness, and high-risk markers for CLL/SLL. This study examined the trends in genomic testing and compared outcomes of first line (1L) CLL patients treated with ibrutinib or CIT in clinical practice. Methods: The nationwide Flatiron Electronic Health Record-derived de-identified database (03/04/2016-08/31/2021) was used to select patients with CLL/SLL who had ≥2 clinic visits and started 1L therapy with ibrutinib or CIT. Patient baseline characteristics prior to 1L initiation were compared between the two treatment groups. Propensity score-based inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences between treatment groups. Kaplan-Meier (KM) analysis was used to evaluate time to next treatment (TTNT) from 1L initiation. Two subgroup analyses were performed among patients with high-risk cytogenetic markers (deletion 17p, 11q or unmutated IGHV) and those without IGHV testing. Results: Overall, the rate of testing for high-risk markers remain suboptimal, while cytogenetic testing for del17p or del11q improved from 52.3% to 74.3%, coinciding with approval of ibrutinib for del17p in 2014, IGHV testing remains infrequent and low at 37.7%. 1882 patients (61.4%) received 1L ibrutinib monotherapy (mean age 71, median follow-up 26 months), and 1182 (38.6%) received a CIT regimen (mean age 68, median follow-up 33 months). More patients treated with ibrutinib had a known high-risk cytogenetic marker (44% vs. 34%), especially in those with deletion 17p (15% vs. 4%), than those treated with CIT. Ibrutinib-treated patients significantly decreased risk of initiating a subsequent treatment by 51% (Table), the high-risk group by 60%, and those with unknown IGHV status by 49%. Conclusions: Consistent with clinical trial evidence, treatment with ibrutinib among 1L CLL patients resulted in a statistically significantly lower risk of initiating subsequent treatment than those treated with CIT, both overall and in the subgroups of patients with high-risk cytogenetic markers and patients without IGHV testing. Assessment of cytogenetic/molecular risk status for appropriate treatment is vital to optimize clinical outcomes, especially in the novel agent era. Recent IGHV testing in community practice to assess genetic risk in CLL remains suboptimal.[Table: see text]
Identifying genetic factors of response and resistance to CDK4/6 inhibitors in metastatic HR+/HER2-breast cancer using real-world data.
Authors: Smita Agrawal, Neeraj Singh, Babu Narayanan
Journal: Journal of Clinical Oncology (2022)

1064 Background: CDK4/6 inhibitors plus endocrine therapy are approved for treatment of HR+/HER2- metastatic breast cancer (MBC) and have shown to provide a significant progression free survival benefit over endocrine therapy alone. But not all patients benefit from this treatment and some develop resistance over time. The molecular mechanisms governing this resistance are poorly understood. We have developed a real world dataset that includes data elements from structured EMR tables as well as deeply curated unstructured data from BC patients (ConcertAI Genome360 BC Dataset) who have been treated with CDK4/6 inhibitors and have undergone DNA sequencing to identify somatic mutations. We have leveraged this linked clinical-genomics dataset to identify genetic drivers of resistance and response to CDK4/6 inhibitors. Methods: This retrospective study uses the Genome360 BC Dataset (N = 1249). The patient’s eligibility to be included in this study (N = 456) was HR+/HER2- MBC patients with age &gt; 18 years treated with at least one of the CDK4/6 inhibitors and have response data based on RECIST criteria (responders = 231, non-responders = 225). For each patient in both cohorts, all pathogenic gene mutations and copy number changes were identified and enrichment analysis was performed. Biomarkers with Z value &gt; 1.96 (p value &lt; 0.05) were considered for further analysis. Pathway analysis was performed using these biomarkers and the CDK4/6 pathway to identify pathways and genes that can potentially be targeted to overcome resistance based on the mutational landscape of the patients receiving therapy. Results: We identified 7 potential segments (similar groups of genes) which predicted response or resistance to CDK4/6 inhibitors. Here we present data on 3 such segments which are closely related. Loss of function mutations in RB1 were enriched in the non-responder population (Z value = 2.33; p value = 0.026; N = 31). This is consistent with previously reported findings. In addition, amplifications and gain of function mutations in MYC and associated genes were also significantly enriched in the non-responder population (Z value = 2.71; P value = 0.01; N = 44). Interestingly, loss of function mutations in TSC1/2 genes which are downstream of MYC were predictors of good response to CDK4/6 inhibitors (Z value = 2.19; P value = 0.036; N = 30), strengthening the role of the parallel MYC signaling pathway in resistance to CDK4/6 inhibitors. Conclusions: Using our Genome360 BC Dataset, we have identified genetic markers affecting response to CDK4/6 inhibitors. In addition to the known role of RB1 in resistance to CDK4/6 inhibitors, the MYC signaling pathway emerged as a strong candidate. Based on these results, patients with mutations in these pathways may benefit from addition of mTOR or PKL1 inhibitors to CDK4/6 inhibitors to overcome resistance and prolong their effect.
Expanding the use of targeted therapy for Urothelial Bladder Cancer (UBC): Non-FGFR3 Receptor Tyrosine Kinase (RTK) Gene Rearrangements (ReAr) and Fusions (Fus)
Authors: A. Necchi, D. Pavlick, G. Bratslavsky, J. Jacob, O. Kravtsov, P. Spiess, P. Grivas, V. Parini, B. Decker, D. Lin, N. Danziger, M. Levy, J. Ross
Journal: European Urology (2022)
Identified potential pathogenic variants of BARD1 in 1449 Chinese high-risk breast cancer patients.
Authors: Rong Wang, Weiwu Ye, Zhanhong Chen, Xiying Shao, Wenming Cao, Xiaojia Wang, Yabing Zheng
Journal: Journal of Clinical Oncology (2022)

e22525 Background: BARD1 (BRCA1-associated ring domain 1), nuclear partner of BRCA1, has been recognized as a breast cancer predisposition gene. Recently, two large-scale population-based case–control studies confirmed that germline loss-of-function mutations in BARD1 were associated with a risk of breast cancer. Since the germline mutation frequency of BARD1 is much less than that of BRCA1/2, the distinct mutation spectrum of BARD1 is still obscure, especially in Chinese breast cancer patients. To verify the utility of BARD1 genetic testing in Chinese population, we assessed the mutational frequency and spectrum of BARD1 in a sequential series of Chinese high-risk breast cancer patients. Methods: A cohort of high-risk breast cancer patients (n = 1449) were collected in Zhejiang Cancer Hospital from 2008 through 2020, including 608 familial breast cancer (BC) cases, 173 bilateral BC cases, 222 triple negative BC cases, 436 early-onset BC cases (≤40 years) and 10 male BC cases. The complete coding sequence and intron–exon boundaries of BARD1 were screened by a 98-gene panel sequencing assay. The SIFT, Polyphen2 and MutationTaster prediction programs were used for analyzing the effect of the variants of unknown significance (VUS) on the BARD1 protein function. Results: A total of three BARD1 pathogenic mutations (c.1348_1349delinsCAT, c.70_71insGT and c.373G &gt; T) were identified, which had been all reported, and accounting for 0.2% (3/1449) in Chinese high-risk breast cancer patients. The frequencies were 0.33% (2/608) and 0.12% (1/841) in familial and non-familial breast cancer patients, respectively. In total, 19 VUSs including 17 missenses, one inframe deletion and one inframe insertion of BARD1 were identified in this study. Based on in silico analysis, nine BARD1 missense variants (c.76A &gt; G, c.1912G &gt; A, c.1693C &gt; T, c.2191C &gt; T, c.127C &gt; A, c.1601C &gt; T, c.443G &gt; A, c.233G &gt; A and c.1972C &gt; T) were classified as potentially damaging. However, the two newly variants c.420_422del and c.68_69insTCCGGGAACGAGCCTCGTTCC still remain VUS, and the other eight variants were classified as benign. Conclusions: Our data presented the germline mutations of BARD1 in a large-scale Chinese high-risk breast cancer population, which accounted for 0.2% in our cohort. Moreover nine potential pathogenic variants were found based on in silico analysis. Clinically, these data may be helpful in genetic counseling of breast cancer patients with BARD1 germline mutation. While the further research on the VUS are needed.
Influence of darolutamide on cabazitaxel systemic exposure.
Authors: Stefan Buck, Niels A.D. Guchelaar, Peter de Bruijn, Inge M. Ghobadi Moghaddam-Helmantel, Esther Oomen De Hoop, Hans M. Westgeest, Paul Hamberg, Danielle Mathijssen-van Stein, Martijn P. Lolkema, Stijn L.W. Koolen, Ronald De Wit, Ron H.J. Mathijssen
Journal: Journal of Clinical Oncology (2022)

5038 Background: Taxane efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients is limited due to resistance development. In preclinical models it has been shown that addition of the androgen receptor signalling inhibitor (ARSI) enzalutamide improves cabazitaxel efficacy. However, we have previously shown that the clinical utility of this combination is hampered by a strong CYP3A4 drug-drug interaction with enzalutamide, resulting in a 22% reduced cabazitaxel systemic exposure. Darolutamide has much weaker CYP3A4 inducing effects and therefore may affect cabazitaxel systemic exposure to a lesser extent. Methods: We investigated the influence of darolutamide on cabazitaxel plasma exposure. mCRPC patients were enrolled on cabazitaxel monotherapy (20 mg/m 2 Q3W) on day 1 and received concomitant darolutamide (600 mg b.i.d.) from day 2 onwards for maximal 12 weeks. During cabazitaxel infusion on day 1, and after 6 and 12 weeks of darolutamide treatment, we measured cabazitaxel systemic exposure via Area Under the Curve from 0 to 24 hours (AUC 0-24h ). Results: Cabazitaxel systemic exposure in 18 patients after 6 weeks of darolutamide was not significantly different compared to prior to darolutamide treatment (AUC 0-24h : -4%; 95%CI -19 – +13%; p = 0.58). Also, after 12 weeks of darolutamide treatment, cabazitaxel systemic exposure was unaltered (AUC 0-24h : +4%; 95%CI -10 – +20%; p = 0.54). Darolutamide plasma concentrations were constant throughout the study (Table). Conclusions: From a pharmacokinetic perspective cabazitaxel and darolutamide can be safely combined in mCRPC patients. Our findings pave the way for testing the efficacy of this promising combination in an era of combination regimens for prostate cancer. Clinical trial information: NL8611. [Table: see text]
Adipsin a regulatory protein found in the extracellular matrix is modulated by hypercholesterolemia in myocardial infarction
Authors: T Padro, M Garcia-Arguinzonis, G Vilahur, E Diaz-Riera, L Badimon
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Agencia Estatal de Investigación (AEI)- Spanish Institute of Health Carlos III, ISCIII; Agencia Estatal de Investigación (AEI)- Spanish Ministry of Economy Competitiveness of Science Background Local inflammation and innate immunity are key features during cardiac remodelling post myocardial infarction (MI). Adipsin, a component of the inflammatory response, is the major activator of the C3-complement pathway and exerts elastolytic activity. Beyond liver, adipsin is mostly secreted from adipocytes, monocytes and macrophages. It is to notice that intramyocardial lipid accumulation alters the fibrotic reparative process of the scar, resulting in larger infarcts and cardiac dysfunction in a pig model. Adipsin could directly contribute to collagen turnover in the cardiac extracellular matrix (ECM) during formation of the post-MI scar. Purpose The role of adipsin in the setting of myocardial infarction remains unknown. Here we investigated adipsin changes (content and activity) in the cardiac ECM of MI pigs and determine whether hypercholesterolemia relates to the turnover of the ECM-collagen pattern in association with the adipsin content. Methods Normo- (NC) and diet-induced hyper- (HC) cholesterolemic animals (N=28) were randomly distributed to MI-induction or sham-operation (N=7 animals/group). MI was induced by 90min closed-chest coronary balloon occlusion. After revascularization, animals were either maintained for 2.5hours or 30days before being sacrificed. Adipsin, C3- activation products (as readout of adipsin activity) and collagen fragmentation products were determined in cardiac ECM-extracts from the ischemic and non-ischemic regions in all pigs. Results Adipsin and C3-activation products (iC3b, C3dg) were consistently detected in the cardiac ECM of sham-operated animals. Detection levels of adipsin, iC3b and C3dg were &amp;gt;2fold higher in HC vs NC pigs (p&amp;lt;0.05) suggesting higher adipsin activity in hearts of animals with high cholesterol levels. NC and HC MI-pigs subjected to 2.5hours reperfusion showed an acute and sharp increase in cardiac adipsin detection in the ischemic region as compared to sham and non-ischemic areas (p&amp;lt;0.05). At 30days post-MI, adipsin content in the scar was comparable to that of sham-operated animals remaining significantly higher in HC vs NC pigs. Yet, adipsin cardiac levels in the scar of HC animals were associated with a lower content of fibrillar collagen-1 (MW: 235kDa) and a higher proportion of proteolytic collagen-fragments (MW: 135-48 kDa) (p&amp;lt;0.05 vs NC pigs) Conclusions Adipsin is a component of the cardiac ECM. Hypercholesterolemia enhances myocardial adipsin content and activity and promotes proteolysis of collagen fibrils in the forming scar contributing to the cardiac remodeling during post-infarction.